WO2023016237A1 - Impureté présente dans de la plinabuline ou préparation de celle-ci, et son utilisation - Google Patents

Impureté présente dans de la plinabuline ou préparation de celle-ci, et son utilisation Download PDF

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WO2023016237A1
WO2023016237A1 PCT/CN2022/107702 CN2022107702W WO2023016237A1 WO 2023016237 A1 WO2023016237 A1 WO 2023016237A1 CN 2022107702 W CN2022107702 W CN 2022107702W WO 2023016237 A1 WO2023016237 A1 WO 2023016237A1
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plinabulin
compound
composition
formula
preparation
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PCT/CN2022/107702
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English (en)
Chinese (zh)
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何成江
张丹扬
毛建民
杜丽华
黄岚
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大连万春布林医药有限公司
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Priority to EP22855220.4A priority Critical patent/EP4385987A1/fr
Priority to CN202280054900.7A priority patent/CN117940418A/zh
Publication of WO2023016237A1 publication Critical patent/WO2023016237A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis

Definitions

  • the invention belongs to the field of medicine, and in particular relates to impurities in plinabulin or its preparations and uses thereof.
  • Plinabulin ((3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazine di Keto
  • phenylahistin a synthetic analogue of the diketopiperazine phenylahistin (phenylahistin) found in marine and terrestrial species of Aspergillus, the structure of which is shown below:
  • Plinabulin is structurally distinct from colchicine and its combretastatin-like analogs (eg, compretastatin phosphate) and at the colchicine-binding site on the tubulin monomer or its vicinity.
  • combretastatin-like analogs eg, compretastatin phosphate
  • plinabulin induces tubulin depolymerization and monolayer permeability in vascular endothelial cells at low concentrations compared with colchicine and have shown that plinabulin induces apoptosis in Jurkat leukemia cells Death.
  • Studies of Plinabulin as a single agent in patients with advanced malignancies lung, prostate and colon cancer demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles.
  • Impurity research is an important part of drug research and development, which runs through the entire process of drug research and development and directly affects the safety, effectiveness and quality controllability of drugs.
  • the quality control of drugs is mainly to control the content of active ingredients and related substances, especially the content of related substances needs to meet the pharmaceutical requirements, and the impurities mainly come from the synthesis process and drug degradation.
  • a high-purity impurity is required to be used as a reference substance to control the quality of the drug that may contain the impurity. Therefore, providing a plinabulin impurity standard is of great significance to the quality control of plinabulin or its pharmaceutical composition.
  • the object of the present invention is to provide a plinabulin impurity, its preparation method, and its application in drug quality control.
  • the first aspect of the present invention provides a compound of formula I
  • the second aspect of the present invention provides a composition, wherein the composition comprises i) plinabulin and ii) the compound of formula I described in the first aspect.
  • the composition comprises: (a) a safe and therapeutically effective amount of plinabulin polymorphs or pharmaceutically acceptable salts thereof, and (b) pharmaceutically acceptable carriers and diluents , an excipient, or a combination thereof.
  • the diluent includes 15-hydroxy polyethylene glycol stearate.
  • the diluent includes propylene glycol.
  • the diluent includes 15-hydroxy polyethylene glycol stearate and propylene glycol.
  • the diluent is 15-hydroxypolyethylene glycol stearate and propylene glycol, wherein, 15-hydroxypolyethylene glycol stearate is about 40% by weight and propylene glycol is about 60% by weight. weight%.
  • the mass ratio of plinabulin to the compound of formula I is 1-10000:10000-1.
  • the content of Plinabulin ranges from 0.01% to 99.99%.
  • the third aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises i') the composition as described in the second aspect and ii') a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled release or sustained release or nano-preparation.
  • the single dose of the composition is about 1 mg to about 300 mg.
  • the inert solvent is selected from: ethanol, ethylene glycol, DMSO, DMF, or combinations thereof.
  • the acid is HCl, HAc, or a combination thereof.
  • reaction temperature is 40-80°C, preferably 50-60°C.
  • the molar ratio of acid to plinabulin is 200:1-20:1, preferably 100:1-15:1.
  • the oxidizing agent is selected from: peroxide, oxygen, or a combination thereof.
  • the fifth aspect of the present invention provides a use of the compound of formula I described in the first aspect, wherein the compound is used as a standard for quality control of plinabulin bulk drug or its preparation.
  • control is to measure the content of the compound of formula I in the plinabulin bulk drug or its preparation by high performance liquid chromatography, and calculate it by area normalization method.
  • FIG. 1 shows the HPLC profiles of Plinabulin formulations
  • FIG. 1 shows the HPLC spectrum of Plinabulin bulk drug after acid degradation.
  • FIG. 3 shows the H NMR spectrum of the impurity in Plinabulin.
  • FIG. 4 shows the mass spectrum of Plinabulin impurities.
  • the inventors unexpectedly discovered for the first time a plinabulin preparation impurity, which also produced corresponding impurities in the acid degradation experiment of plinabulin bulk drug.
  • the inventor destroys the plinabulin bulk drug under neutral and acidic conditions in the presence of an oxidant, and separates and purifies it to obtain the plinabulin impurity.
  • the present invention has been accomplished.
  • RT retention time
  • RRT means relative retention time
  • API means a stock solution
  • NPI-2602 The structure of NPI-2602 is shown below
  • the plinabulin composition of the present invention refers to a composition comprising plinabulin and a compound of formula I.
  • the mass ratio of Plinabulin to the compound of formula I is 1-10000:10000-1, preferably 1:1000 to 1000:1; more preferably 1:500 to 500:1; more preferably Earth, 1:100 to 100:1.
  • the content of Plinabulin is in the range of 0.01% to 99.99%, based on the total weight of the composition; preferably 0.1% to 99.9%; more preferably 99.80% to 99.99%; more preferably 99.90% to 99.95% .
  • the content of plinabulin impurities ranges from 0.01% to 99.99%, based on the total weight of the composition; preferably 0.1% to 99.9%; more preferably 0.20% to 0.01%; more preferably 0.1 % to 0.05%.
  • the compositions may also include one or more pharmaceutically acceptable diluents.
  • a pharmaceutically acceptable diluent may include (15-hydroxypolyethylene glycol stearate, kolliphor).
  • the pharmaceutically acceptable diluent may include propylene glycol.
  • pharmaceutically acceptable diluents may include kolliphor and propylene glycol.
  • the pharmaceutically acceptable diluent can include kolliphor and propylene glycol, wherein the kolliphor is about 40% by weight and the propylene glycol is about 60% by weight, based on the total weight of the diluent.
  • the composition may also include one or more other pharmaceutically acceptable excipients.
  • some embodiments include a pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of plinabulin polymorph or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent , an excipient, or a combination thereof.
  • embodiments include the co-administration of the plinabulin polymorph and the additional therapeutic agent in separate compositions or in the same composition. Accordingly, some embodiments include a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises: (a) a safe and therapeutically effective amount of a polymorph of plinabulin or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof; and a second pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of an additional therapeutic agent and (b) a pharmaceutically acceptable carrier , diluent, excipient or combination thereof.
  • Some embodiments include a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a safe and therapeutically effective amount of a polymorph of plinabulin or a pharmaceutically acceptable salt thereof; (b) a safe and therapeutically effective amount of an additional therapeutic agent; and (c) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • the dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nano-preparation.
  • Administration of the pharmaceutical compositions described herein may be via any acceptable means of administering agents (for similar uses), including, but not limited to, oral, sublingual, buccal, subcutaneous, intravenous, intranasal, topical, Transdermal, intradermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are commonly used in the treatment of indications which are the subject of preferred embodiments.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art.
  • the use of such media or agents in therapeutic compositions is contemplated, except for any conventional media or agents that are incompatible with the active ingredient.
  • various adjuvants commonly used in the art for example, may be included. Considerations for including various components in pharmaceutical compositions are described, e.g., in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated by reference in its entirety This article.
  • substances that can be used as pharmaceutically acceptable carriers or components thereof are: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose Sodium, ethylcellulose, and methylcellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil , olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; Coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphat
  • compositions described herein are preferably presented in unit dosage form.
  • a "unit dosage form" is a composition containing an amount of a compound or composition suitable for administration in a single dosage to an animal, preferably a mammalian subject, in accordance with good medical practice.
  • a single dosage form or unit dosage form does not mean that the dosage form is administered once per day or once per course of treatment.
  • the dosage form is contemplated to be administered once, twice, three times or more per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or as a continuous infusion, and may be administered over a course of More than one administration during the period, but a single administration is not specifically excluded.
  • the formulation does not take into account the entire course of treatment and that such determinations should be left to those skilled in the therapeutic art rather than the formulation art.
  • compositions as described above may be in any of a variety of suitable forms for various routes of administration, for example, for oral, sublingual, buccal, nasal, rectal, topical (including transdermal and intradermal ), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parental routes of administration.
  • oral and nasal compositions include compositions administered by inhalation and prepared using appropriate techniques.
  • pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, solubilizers, surfactants and encapsulating substances.
  • Optional pharmaceutically active materials may be included which do not substantially interfere with the activity of the compound or composition.
  • the amount of carrier used in conjunction with the compound or composition is sufficient to provide a practical amount of the material for administration per unit dose of the compound.
  • Techniques and compositions for preparing dosage forms suitable for use in the methods described herein are described in the following reference, which is incorporated herein by reference: Modern Pharmaceuticals, 4th Edition, Chapters 9 and 10 (Banker and Rhodes, Ed., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
  • oral dosage forms can be used including, for example, solid forms such as tablets, capsules (eg, liquid gel capsules and solid gel capsules), granules and bulk powders. Tablets may be compressed, molded, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, flow-inducing agents and fusion aids.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules, containing suitable solvents, preservatives , emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art.
  • Tablets usually contain conventional pharmaceutically compatible adjuvants as inert diluents, for example: calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, such as starch, gelatin and sucrose; disintegrants, such as Starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture.
  • colorants such as FD&C dyes can be added.
  • sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint, sucrose and fruit flavors are useful adjuvants.
  • Capsules generally contain one or more solid diluents disclosed above. The choice of carrier components depends on minor considerations such as taste, cost and storage stability, which are not critical and can be readily accomplished by those skilled in the art.
  • Oral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • Pharmaceutically acceptable carriers suitable for use in preparing such compositions are well known in the art.
  • Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICE LRC-591, tragacanth, and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and
  • Typical preservatives include methylparaben and sodium benzoate.
  • Oral liquid compositions may also contain one or more of the ingredients disclosed above, such as sweetening, flavoring and coloring agents.
  • compositions may also be coated by conventional methods, usually with pH-dependent or time-dependent coatings, so that the release of the composition in the gastrointestinal tract is near the desired topical application, or at different times to Prolong desired activity.
  • dosage forms typically include, but are not limited to, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, One or more of wax and shellac.
  • compositions described herein may optionally include other pharmaceutical actives.
  • compositions useful for achieving systemic delivery of the compounds of the present application include sublingual, buccal and nasal dosage forms.
  • Such compositions typically contain one or more of: soluble filler substances, such as sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl base methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • Liquid compositions for topical ophthalmic use will be formulated such that they can be applied topically to the eye. Comfort can be maximized wherever possible, but sometimes formulation considerations (eg, drug stability) may not allow optimum comfort. Where comfort cannot be maximized, liquids can be formulated such that they are tolerated by the patient for topical ophthalmic use.
  • ophthalmically acceptable fluids may be packaged for single use, or contain a preservative to prevent contamination during multiple uses.
  • solutions or drugs are usually prepared using saline solution as the main carrier.
  • Ophthalmic solutions preferably can be maintained at a comfortable pH with suitable buffer systems.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • a variety of useful carriers can be used in the ophthalmic formulations disclosed herein. These carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose, hydroxyethylcellulose and purified water.
  • Tonicity adjusting agents can be added as desired or convenient. These include, but are not limited to, salts (especially sodium chloride, potassium chloride), mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjusting agent.
  • buffers include acetate buffers, citrate buffered saline, phosphate buffers and borate buffers. Acids or bases can be used to adjust the pH of these formulations as necessary.
  • Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
  • excipient components that may be included in ophthalmic formulations are chelating agents.
  • a useful chelating agent is disodium ethylenediaminetetraacetic acid (EDTA), but other chelating agents may be used instead or in combination.
  • EDTA disodium ethylenediaminetetraacetic acid
  • topical formulations may consist of pharmaceutical carriers, co-solvents, emulsifiers, penetration enhancers, preservative systems and emollients.
  • the composition described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as physiological saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as physiological saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl and citric acid.
  • the pH of the final composition is between 2 and 8, or preferably between 4 and 7.
  • Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA.
  • excipients present in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, mannitol and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are hereby incorporated by reference in their entirety.
  • Antimicrobial agents including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol may also be included to obtain a bacteriostatic or fungicidal solution.
  • compositions for intravenous administration may be provided to the caregiver in the form of one or more solids which are diluted with a suitable diluent (eg sterile water, normal saline or aqueous dextrose) immediately prior to administration. Do the refactoring.
  • a suitable diluent eg sterile water, normal saline or aqueous dextrose
  • the compositions are provided in solutions that are amenable to parenteral administration.
  • the composition is provided as a further diluted solution prior to administration.
  • the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately. reagent.
  • a single dose of the composition or other therapeutic agent may be from about 5 mg/m 2 to about 150 mg/m 2 body surface area, from about 5 mg/m 2 to about 100 mg/m 2 body surface area, from about 10 mg/m 2 to about 100 mg/ m2 body surface area, about 10 mg/ m2 to about 80 mg/ m2 body surface area, about 10 mg/ m2 to about 50 mg/ m2 body surface area, about 10 mg/ m2 to about 40 mg/ m2 body surface area , about 10 mg/m 2 to about 30 mg/m 2 body surface area, about 13.5 mg/m 2 to about 100 mg/m 2 body surface area, about 13.5 mg/m 2 to about 80 mg/m 2 body surface area, about 13.5 mg/m 2 2 to about 50 mg/ m2 body surface area, about 13.5 mg/ m2 to about 40 mg/ m2 body surface area, about 13.5 mg/ m2 to about 30 mg/ m2 body surface area, about 15 mg/ m2 to about 80 mg
  • a single dose of the composition or other therapeutic agent may range from about 13.5 mg/m 2 to about 30 mg/m 2 body surface area. In some embodiments, a single dose of the composition or other therapeutic agent may be about 5 mg/m 2 , about 10 mg/m 2 , about 12.5 mg/m 2 , about 13.5 mg/m 2 , about 15 mg/m 2 , about 17.5mg/m 2 , about 20mg/m 2 , about 22.5mg/m 2 , about 25mg/m 2 , about 27.5mg/m 2 , about 30mg/m 2 , about 40mg/m 2 , about 50mg/m 2 , About 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , or about 100 mg/m 2 body surface area.
  • a single dose (one-time dose) of the composition or other therapeutic agent may be from about 1 mg to about 300 mg, from about 5 mg to about 200 mg, from about 7.5 mg to about 200 mg, from about 10 mg to about 100 mg, about 15 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 10 mg to about 80 mg, about 15 mg to about 80 mg, about 20 mg to about 80 mg, about 30 mg to about 80 mg, about 40 mg to About 80 mg, about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, or about 40 mg to about 60 mg.
  • a single dose of a composition or other therapeutic agent may be from about 20 mg to about 60 mg, from about 27 mg to about 60 mg, from about 20 mg to about 45 mg, or from about 27 mg to about 45 mg.
  • a single dose of a composition or other therapeutic agent may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.
  • the period of administration may be a multi-week treatment cycle as long as the tumor remains manageable and the regimen is clinically acceptable.
  • a single dose of the composition or other therapeutic agent may be administered once a week, and preferably, once each of Days 1 and 8 of a three-week (21-day) treatment cycle or at Dosing on Day 1 of a three-week (21-day) treatment cycle.
  • a single dose of a composition or other therapeutic agent may be administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or in one, two, three Administered daily for weekly, four-week or five-week treatment cycles.
  • the administration can be on the same or different days of each week in the treatment cycle.
  • Treatment cycles may be repeated as long as the regimen is clinically acceptable.
  • the treatment cycle is repeated n times, where n is an integer from 2 to 30. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • a new treatment cycle can be administered immediately after completion of a previous treatment cycle. In some embodiments, a new treatment cycle may be administered some time after completion of a previous treatment cycle.
  • compositions described herein may be used in combination with other therapeutic agents.
  • compositions described herein may be administered or used in combination with other treatments such as chemotherapy, radiation, and biological therapy.
  • the Plinabulin bulk drug was acid-destructed, and the destroyed API was detected by the analysis method for the related substances of the Plinabulin bulk drug, and the impurity at RRT0.61 was found, and it was separated and purified.
  • the Plinabulin impurity is prepared by the following method
  • plinabulin reacts with an oxidizing agent (such as peroxides, such as H 2 O 2 ) to obtain the formula I compounds and benzaldehyde.
  • an oxidizing agent such as peroxides, such as H 2 O 2

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Abstract

La présente invention concerne une impureté présente dans de la plinabuline ou une préparation de celle-ci, et son utilisation. L'impureté a la structure telle que représentée dans la formule I, et peut être obtenue par dégradation oxydative de plinabuline dans des conditions neutres ou acides, ayant une grande importance dans le contrôle qualité de la plinabuline ou une préparation de celle-ci.
PCT/CN2022/107702 2021-08-13 2022-07-25 Impureté présente dans de la plinabuline ou préparation de celle-ci, et son utilisation WO2023016237A1 (fr)

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EP22855220.4A EP4385987A1 (fr) 2021-08-13 2022-07-25 Impureté présente dans de la plinabuline ou préparation de celle-ci, et son utilisation
CN202280054900.7A CN117940418A (zh) 2021-08-13 2022-07-25 普那布林或其制剂中的杂质及其用途

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CN202110932963.5A CN115703763A (zh) 2021-08-13 2021-08-13 普那布林或其制剂中的杂质及其用途

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1934101A (zh) * 2004-02-04 2007-03-21 尼瑞斯药品公司 脱氢苯基阿夕斯丁及其类似物以及脱氢苯基阿夕斯丁及其类似物的合成
CN114349740A (zh) * 2022-01-17 2022-04-15 中国海洋大学 一种微管蛋白抑制剂普那布林异构体杂质的制备方法及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1934101A (zh) * 2004-02-04 2007-03-21 尼瑞斯药品公司 脱氢苯基阿夕斯丁及其类似物以及脱氢苯基阿夕斯丁及其类似物的合成
CN114349740A (zh) * 2022-01-17 2022-04-15 中国海洋大学 一种微管蛋白抑制剂普那布林异构体杂质的制备方法及其应用

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Goodman and Gilman's: The Pharmacological Basis of Therapeutics", 1990, PERGAMON PRESS
"Modern Pharmaceutics", 2002
"Remington's The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
ANSEL: "Introduction to Pharmaceutical Dosage Forms", 2004
LIEBERMAN ET AL.: "Pharmaceutical Dosage Forms: Tablets", 1989
MACHIN PETER J, SAMMES PETER G: "Pyrazine Chemistry. Part VIII. Oxidations involving 3-Arylmethylene- piperazine-2,5-diones", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, ROYAL SOCIETY OF CHEMISTRY, CAMBRIDGE, UK, no. 6, 1 January 1976 (1976-01-01), Cambridge, UK , pages 628 - 634, XP093034307, ISSN: 0300-922X *
MARCUCCIO S M, ELIX J A: "PYRAZINE CHEMISTRY. V SYNTHESIS OF METHYLANHYDROPICROROCCELLIN AND DIMETHYLPICROROCCELLIN", AUSTRALIAN JOURNAL OF CHEMISTRY, C S I R O PUBLISHING, AU, vol. 38, no. 12, 1 January 1985 (1985-01-01), AU , pages 1785 - 1796, XP009021127, ISSN: 0004-9425 *
NEMA ET AL.: "Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions", PDA J PHARM SCI AND TECH, vol. 65, 2011, pages 287 - 332, XP009166667, DOI: 10.5731/pdajpst.2011.00634
POWELL ET AL.: "Compendium of Excipients for Parenteral Formulations", PDA J PHARM SCI AND TECH, vol. 52, 1998, pages 238 - 311, XP009119027

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CN115703763A (zh) 2023-02-17
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